Age-related macular degeneration (AMD) is the leading cause of irreversible severe central visual loss in the aged population. Various studies suggest that AMD has a significant genetic component. Current evidence supports the hypothesis that gene variation causes predisposition to the disease. We initiated the project in early 2003 by recruiting advanced AMD patients and normal controls. So far over 300 subjects have been enrolled and 40 histopathological cases with AMD were collected. We are comparing the allelic frequencies of single nucleotide polymorphisms (SNPs) within candidate genes between AMD and control subjects followed by the functional study of these SNPs by in vitro and/or in vivo experiments. Through this approach, we will attempt to identify genetic risk factors of AMD and understand the role of these gene variations in the pathogenesis of the disease. In FY2005, we have accomplished the following: 1. Completion of 16 SNPs typing; 2. Confirmation of an association between ERCC6 SNP and AMD and characterization of the altered promotor function due to the SNP in ERCC6; 3. Functional studies on the recombinants of ApoE SNP isotypes on the human RPE cell; 4. Characterization of the retinal lesion of the CX3CR1/CCL2 double knock-out mice, a murine model of AMD, which we developed. We have reported our findings in the literature and are preparing several more manuscripts.